The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca2+ stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation

Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.Peer reviewe

Isoflurane produces antidepressant effects and induces TrkB signaling in rodents

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3 beta (GSK3 beta). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.Peer reviewe

Kainate receptors in the developing neuronal networks

Kainate receptors (KARs) are highly expressed in the immature brain and have unique developmentally regulated functions that may be important in linking neuronal activity to morphogenesis during activitydependent fine-tuning of the synaptic connectivity. Altered expression of KARs in the developing neural network leads to changes in glutamatergic connectivity and network excitability, which may lead to longlasting changes in behaviorally relevant circuitries in the brain. Here, we summarize the current knowledge on physiological and morphogenic functions described for different types of KARs at immature neural circuitries, focusing on their roles in modulating synaptic transmission and plasticity as well as circuit maturation in the rodent hippocampus and amygdala. Finally, we discuss the emerging evidence suggesting that malfunction of KARs in the immature brain may contribute to the pathophysiology underlying developmentally originating neurological disorders.Peer reviewe

Wpływ impulsów elektromagnetycznych dużej mocy na właściwości strukturalne, chemiczne i fizykochemiczne minerałów ziem rzadkich

The investigation of the structural-chemical state and sorption properties modification of columbite and eudialite surface under the impact of high-power nanosecond pulses (HPEMP) was performed using XPS and FTIR. It was defined that preliminarily treatment of rare-metal minerals with high-power nanosecond pulses is promising tool for the directional changes in their physicochemical and structural-chemical properties as it was confirmed by the increasing of mineral's sorption activity.Badanie modyfikacji stanu strukturalno-chemicznego i właściwości sorpcyjnych powierzchni kolumbitu i eudialitu pod wpływem impulsów nanosekundowych o dużej mocy (HPEMP) przeprowadzono za pomocą XPS i FTIR. Ustalono, że wstępna obróbka minerałów metali rzadkich impulsami nanosekundowymi o dużej mocy jest obiecującym narzędziem do kierunkowych zmian ich właściwości fizykochemicznych i strukturalno-chemicznych, co zostało potwierdzone przez zwiększenie aktywności sorpcyjnej minerału

Efekty modyfikacji powierzchni naturalnych siarczków za pomocą impulsów elektromagnetycznych dużej mocy

Surface changes in naturally occurring metal sulphides (pyrite, arsenopyrite, sphalerite, chalcopyrite, galena and molybdenite) due to the treatments from high – power electromagnetic pulses (HPEMP) at varying times were studied using XPS. Analysis of the obtained results revealed common patterns and differences in surface transformations. The transformations were found to include two main stages. The first stage were observed at low treatment intensities (up to N ~ 103 pulses). At this stage formation and accumulation in the surface layer of the nonstoichiometric sulphide phase, oxides and hydroxides, as well as elemental (polysulfide) sulphur and / or metastable sulphur species (thiosulfate, sulphite) were observed. The second stage (N ≥ 3 · 103 pulses) is characterized by the removal of sulphur species and renewal of the mineral surface (sulfidization). The application of HPEMP treatment to improve flotation selectivity is supported by single-mineral flotation tests. Changes in floatability as a result of HPEMP treatment are principally explained by surface phase changes.Zmiany powierzchni w naturalnie występujących siarczkach metali (piryt, arsenopiryt, sfaleryt, chalkopiryt, galena i molibdenit) w wyniku obróbki impulsami elektromagnetycznymi o dużej mocy (HPEMP) w różnym czasie badano przy użyciu XPS. Analiza uzyskanych wyników ujawniła typowe wzory i różnice w transformacjach powierzchniowych. Stwierdzono, że transformacje obejmują dwa główne etapy. Pierwszy etap obserwowano przy niskiej intensywności działania impulsami (do N ~ 103 impulsów). Na tym etapie zaobserwowano tworzenie i akumulację w warstwie powierzchniowej niestechiometrycznej fazy siarczkowej, tlenków i wodorotlenków, a także siarki elementarnej (polisiarczkowej) i / lub metastabilnej (tiosiarczan, siarczyn). Drugi etap (N ≥ 3 · 103 impulsów) charakteryzuje się usuwaniem rodzajów siarki i odnawianiem powierzchni mineralnej (siarczkowanie). Zastosowanie obróbki HPEMP w celu poprawy selektywności flotacji jest poparte testami flotacji pojedynczych minerałów. Zmiany flotowalności w wyniku obróbki HPEMP są wyjaśnione zmianami fazy powierzchniowej

The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca2+ stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation